Some thoughts on fragments

Over the past week I was in London, England. While there, I attended the OBC editorial board meeting, which I now chair. The scientific highlight of the trip was my visit to Cambridge, where I had a chance to give a lecture at Astex Pharmaceuticals, a remarkable company that has been making tremendous strides in the area of fragment-based drug discovery. My former student, Jeff St. Denis, is working there now. Jeff made this visit happen (as well as a round of golf at the Cambridge Meridian Club –, which was a ton of fun).

One notable concept I heard about from the scientists at Astex is that of a minimal pharmacophore. This corresponds to a system of classifying small heterocycles based on their capacity to engage targets. It  makes sense that some scaffolds are way “better” than others and, as you might imagine, the reasons are myriad. Astex has amassed an impressive portfolio of small molecule fragments they call Pyramid. I have always wanted to see a study that would put forth comparative metrics to gauge different scaffolds. Astex’s Pyramid is a tremendous resource in this regard. A paper describing the details of this methodology is in the works. However, I can illustrate what this is all about using one of the papers that are already out there. Take a look at the XIAP inhibitor study published by Astex not long ago. The chlorine substituent present in the molecule shown below has enabled a 50-fold jump in potency. While this might seem to just be a decent medicinal chemistry accomplishment, there is something to note about certain structural types that consistently display a knack to interact with protein pockets, be it via hydrogen bonds, stacking interactions, or other kinds of intermolecular forces. The framework that exists at Astex enables classification of weakly bound fragments and their comparative analysis. I also learned that computational assessment of the ability of different fragments to interact with their targets continues to be a challenge. Apparently, we are just not there yet in terms of fundamental understanding of weak interactions.

By the way, the final compound described by Astex in the paper below shows activity in a tumor xenograft model at a dose of 100mg/kg i.p., which is really impressive.


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